King's College London

Research portal

Divergent effects of genetic and pharmacological inhibition of Nox2 NADPH oxidase on insulin resistance-related vascular damage

Research output: Contribution to journalArticle

Azhar Maqbool, Nicole T. Watt, Natalie Haywood, Hema Viswambharan, Anna Skromna, Natalia Makava, Asjad Visnagri, Heba M. Shawer, Katherine Bridge, Shovkat K. Muminov, Kathryn Griffin, David J. Beech, Stephen B. Wheatcroft, Karen E. Porter, Katie J. Simmons, Piruthivi Sukumar, Ajay M. Shah, Richard M. Cubbon, Mark T. Kearney, Nadira Y. Yuldasheva

Original languageEnglish
Pages (from-to)C64-C74
JournalAmerican Journal of Physiology - Cell Physiology
Volume318
Issue number1
DOIs
Publication statusPublished - Jul 2020

King's Authors

Abstract

Maqbool A, Watt NT, Haywood N, Viswambharan H, Skromna A, Makava N, Visnagri A, Shawer HM, Bridge K, Muminov SK, Griffin K, Beech DJ, Wheatcroft SB, Porter KE, Simmons KJ, Sukumar P, Shah AM, Cubbon RM, Kearney MT, Yuldasheva NY. Divergent effects of genetic and pharmacological inhibition of Nox2 NADPH oxidase on insulin resistance-related vascular damage. Am J Physiol Cell Physiol 319: C64-C74, 2020. First published May 13, 2020; doi:10.1152/ajpcell.00389.2019.-Insulin resistance leads to excessive endothelial cell (EC) superoxide generation and accelerated atherosclerosis. The principal source of superoxide from the insulin-resistant endothelium is the Nox2 isoform of NADPH oxidase. Here we examine the therapeutic potential of Nox2 inhibition on superoxide generation in saphenous vein ECs (SVECs) from patients with advanced atherosclerosis and type 2 diabetes and on vascular function, vascular damage, and lipid deposition in apolipoprotein E-deficient (ApoE-/-) mice with EC-specific insulin resistance (ESMIRO). To examine the effect of genetic inhibition of Nox2, ESMIRO mice deficient in ApoE-/- and Nox2 (ESMIRO/ApoE-/-/Nox2-/y) were generated and compared with ESMIRO/ApoE-/- Nox2+/y littermates. To examine the effect of pharmacological inhibition of Nox2, we administered gp91dstat or scrambled peptide to ESMIRO/ApoE-/- mice. SVECs from diabetic patients had increased expression of Nox2 protein with concomitant increase in superoxide generation, which could be reduced by the Nox2 inhibitor gp91dstat. After 12 wk Western diet, ESMIRO/ ApoE-/-/Nox2-/y mice had reduced EC superoxide generation and greater aortic relaxation to acetylcholine. ESMIRO/ApoE-/-/ Nox2-/y mice developed more lipid deposition in the thoraco-abdominal aorta with multiple foci of elastin fragmentation at the level of the aortic sinus and greater expression of intercellular adhesion molecule-1 (ICAM-1). Gp91dstat reduced EC superoxide and lipid deposition in the thoraco-abdominal aorta of ESMIRO/ ApoE-/- mice without causing elastin fragmentation or increased ICAM-1 expression. These results demonstrate that insulin resistance is characterized by increased Nox2-derived vascular superoxide. Complete deletion of Nox2 in mice with EC insulin resistance exacerbates, whereas partial pharmacological Nox2 inhibition protects against, insulin resistance-induced vascular damage.

View graph of relations

© 2018 King's College London | Strand | London WC2R 2LS | England | United Kingdom | Tel +44 (0)20 7836 5454